The prior art on cyanoacrylate tissue adhesives has covered many aspects relating to monomer synthesis, preparation and the stabilization against premature anionic and free-radical polymerization of absorbable and non-absorbable tissue adhesive formulations, as well as their tailored modification for effective use, mostly, for topical applications in animals and humans. However, since the development of absorbable cyanoacrylate tissue adhesives, a great deal of interest was directed to the use of polymeric modifiers to impart certain clinically useful properties, which are most pertinent to the instant invention. More specifically, the prior art on absorbable alkoxyalkyl cyanoacrylate-based tissue adhesive/sealant formulations dealt with polymeric modifiers such as (1) oxalate polymers of triethylene glycol (U.S. Pat. No. 5,350,798); (2) oxalate polymers of polyethylene glycols having an average degree of polymerization in excess of 4 (U.S. Pat. No. 6,723,114); (3) poly(2-ethylhexyl methacrylate), poly(vinyl acetate) and lactic acid-caprolactone copolymers (U.S. Pat. No. 6,433,096; and (4) trimethylene carbonate-based polymers (U.S. Pat. No. 6,299,631). The prior art also dealt with stabilized cyanoacrylate-based compositions comprising one or more acidic compound(s) or precursor(s) thereof to maximize the stability of adhesives during storage regardless of the chemical structure of the ester groups (U.S. Pat. Nos. 7,083,634; 6,512,023; 4,125,494). All the absorbable tissue adhesive formulations disclosed in the prior art were comprised predominantly of alkoxy cyanoacrylate monomers which are known to undergo absorption in the biologic environment. The presence of the hydrophilic ether linkage in the alkoxyalkyl cyanoacrylates made them different from all known hydrophobic alkyl cyanoacrylates, in terms of the superior spreadability on biological tissues. This, in turn, minimizes the required adhesive formulation mass per unit area of treated biological tissues. Meanwhile, certain members of alkyl cyanoacrylate groups can provide a distinctly strong adhesive joint upon anionic polymerization in the biologic environment when used as non-absorbable tissue adhesives. This prompted blending small amounts of one or more alkyl cyanoacrylate(s) with established absorbable tissue adhesive formulations of the prior art to improve the initial adhesive joint strength and allow modulating the retention of the adhesive joint holding strength profile, in vivo, without compromising, significantly, the spreadability of the liquid formulation on biological tissues and the bioabsorption of the polymerized solid products as described in U.S. Pat. No. 7,351,426. More specifically, the latter patent dealt with absorbable tissue adhesive compositions comprising one or more alkoxyalkyl cyanoacrylate-based formulation(s) as a major component and one or more alkyl cyanoacrylate(s) as the minor component of said compositions.
Collective analysis of the prior art, discussed above, dealing with both absorbable and non-absorbable cyanoacrylate tissue adhesive/sealant formulations as it pertains specifically to acidic or acid-forming additives used for shielding against premature anionic polymerization and polymeric modifiers indicate that (1) virtually all the acidic or acid-forming additives are simple organic compounds; (2) all polymeric modifiers comprise essentially neutral polymeric chains; and (3) the acidic (e.g., acetic acid and mineral acids) or acid-forming additives and polymeric modifiers are used independently to achieve two distinctly different functions. Thus, consistent calls to simplify clinically important cyanoacrylate tissue adhesive formulations and recent availability of functionalized and, particularly, carboxylic acid-bearing copolyester(s) (U.S. Pat. No. 7,138,464) prompted the exploration of the subject of the instant invention, dealing with the use of multipurpose polymeric rheology modifiers that can also shield against premature polymerization.